Prior Stem Cell Transplant Research Articles

Healthcare Utilization (HRU) and Costs Among Multiple Myeloma (MM) Patients (Pts) Receiving Second or Subsequent Line Treatment (Tx) with Carfilzomib (CAR) or Pomalidomide (POM)

Background A recent retrospective study compared healthcare outcomes and costs in pts with MM receiving CAR or POM using health insurance claims data and reported that CAR pts had higher healthcare costs than POM pts (Parikh ASCO 2016). The results of this analysis have not been confirmed by other investigators.Objective To compare HRU and costs among pts receiving monotherapy with CARor POM +/-dexamethasone (dex) as 2nd or subsequent Tx for MM in the US using a health insurance claims database.Methods This was a retrospective observational study using the MarketScan® database. Pts were adults with MM (ICD-9-CM code 203.0) who initiated MM Tx, including CAR, POM, bortezomib, lenalidomide, thalidomide, and other chemotherapies (CT) for MM, between Jan 1, ’06 and Dec 31, ’14. Pts were excluded for (1) Receipt of a MM Tx before the first MM diagnosis date (Dx date) (2) enrollment gap during the 180-days before Dx date, or between Dx date and the first day on Tx, or the 30 days after Tx initiation, or (3) age <18 y at Tx initiation.Medical/pharmacy claims for MM Tx including CT were tracked for each pt since Tx initiation. After initiation of a first treatment, subsequent lines of therapy (LOT) were identified based on evidence of a new Tx after 90 days since LOT initiation, or >90-day gap in Tx. For each pt with ≥1 CAR or POM LOT, the first LOT with CAR or POM was defined as the index LOT. The date of initiation of this LOT was defined as index date. Pts with CAR or POM as 1st line Tx or in combination with other CT (excluding dex) or with stem cell transplant (SCT) during the index LOT were excluded. Monthly HRU and costs during the index LOT (total, on Tx, off Tx) were compared for pts receiving monotherapy (+/- dex) with CAR vs. POM using inverse probability of treatment weights (IPTW) to obtain average treatment effect (ATE) estimates controlling for measured baseline covariates. IPTWs were based on propensity scores for receipt of CAR estimated by logistic regression with LOT, age, sex, region, plan type, Charlson index, comorbidities, pre-index healthcare cost, and receipt of prior SCT as covariates.Results We identified 114 CAR and 144 POM pts. CAR pts were more likely to receive index Tx in 2nd vs. subsequent LOT, initiate LOT after 2013, be male, and have chronic renal disease, anemia, and diabetes. POM pts were more likely to have prior SCT, chronic pain, and coronary heart disease. Based on examination of standardized differences, IPTW samples were well balanced in baseline characteristics. IPTW adjusted mean monthly total healthcare costs were $19,776 with POM vs. $17,321 with CAR (difference=-$2,455, p=0.52) (Table). Consistent with its mode of administration, the adjusted mean monthly numbers of visits and costs of Tx administration were greater for CAR. The adjusted mean monthly number prescriptions (Rx) were greater for POM vs. CAR. Otherwise, there were no statistically significant differences between groups in adjusted mean monthly total HRU and costs.Conclusions IPTW-adjustedmonthlyHRU and costs do not vary significantly for pts receiving monotherapy with CAR or POM +/- dex for 2nd or subsequent line Tx for MM. To avoid potential bias, treatment comparisons using real world evidence require consideration of patient characteristics that may influence treatment choices and outcomes. [Display omitted] DisclosuresPanjabi:Amgen, Inc.: Employment, Equity Ownership. Hagiwara:Amgen, Inc.: Research Funding. Delea:Amgen, Inc.: Research Funding.

Matching-Adjusted Indirect Comparison of Relative Efficacies Is Feasible and Useful in the Multiple Myeloma Therapy Landscape: A Comparison of Pomalidomide Plus Low-Dose Dexamethasone Versus Daratumumab

INTRODUCTION: Several new agents and regimens are available for the treatment of relapsed refractory multiple myeloma (RRMM). Comparison of all these is not feasible, yet therapeutic selections need to be made for optimal patient care. Both the MM-002 (Richardson et al., 2014) and MM-003 (San Miguel et al., 2013) trials have demonstrated the clinical benefits of pomalidomide plus low-dose dexamethasone (POM+LoDEX) in improving survival outcomes for patients with RRMM who had received ≥2 prior lines of therapy. Daratumumab (DARA) monotherapy was approved in the US for the treatment of RRMM patients, based on the results of a single-arm trial (SIRIUS) (Lonial et al., 2016). To date, there are no head-to-head studies comparing POM+LoDEX with DARA. We performed an indirect comparison of the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between POM+LoDEX and DARA in RRMM patients with ≥2 (median of 5) prior lines of therapy.METHODS: Matching-adjusted indirect comparison (MAIC) (Ishak et al., 2015; Signorovitch et al., 2012) is a method used to conduct indirect comparisons between relative efficacies of treatments after adjusting for imbalances across trials where the study populations were roughly similar. To perform a MAIC, it is necessary that the selected studies are compatible. Both MM-002 and SIRIUS were phase II trials and included mainly patients from North America, while other geographic regions were more widely represented in the phase III MM-003 trial. Thus, the MAIC was conducted using individual patient data from the intention-to-treat (ITT) population of POM+LoDEX from MM-002 and published aggregate data on patient characteristics and outcomes for the ITT population of DARA from SIRIUS. A propensity-score logistic regression equation was used to re-weight the POM+LoDEX patients such that their aggregate characteristics matched exactly those in SIRIUS for all prognostic factors (i.e., full set) which were available in both studies. These factors included age, gender, race, disease duration, immunoglobulin heavy chain type, Eastern Cooperative Oncology Group (ECOG) performance status, plasmacytoma, creatinine clearance, number of prior therapy lines, prior stem cell transplantation, and refractoriness to bortezomib, lenalidomide, or both. The relative treatment effects were estimated with a weighted logistic regression model for ORR and weighted Cox regression models for PFS and OS. Sensitivity analyses were also conducted by matching on only important prognostic factors (i.e., reduced set), identified from multivariate regression analyses for each endpoint.RESULTS: MM-002 and SIRIUS were generally similar in design and had sufficient overlap in baseline characteristics to allow adjustment for potential confounding. Most prognostic factors were similar between the two arms. However, patients on POM+LoDEX had worse ECOG status, while more patients on DARA had a plasmacytoma and creatinine clearance <60 mL/min and were refractory to lenalidomide, bortezomib, or both. After re-weighting, the aggregate patient characteristics for patients receiving POM+LoDEX matched those reported for DARA. The results from the analyses adjusting for all available characteristics showed no statistically significant differences in ORR, PFS, or OS between the two treatments. Similar findings were obtained by adjusting for important prognostic factors only (Table 1). OS results should be interpreted with caution as subsequent treatments cannot be adjusted for in a MAIC analysis.CONCLUSIONS: This analysis suggests that POM+LoDEX and DARA have similar clinical benefits with respect to ORR, PFS, and OS in RRMM patients with ≥2 prior lines of therapy. Treatment choice may be made between these two based on factors other than efficacy alone. MAIC analysis may be helpful in therapeutic decisions where direct comparative trials are not available, however as with any non-randomized study potential for residual confounding may still exist. [Display omitted] DisclosuresParikh:Celgene Corporation: Employment, Equity Ownership, Research Funding. Proskorovsky:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Krotneva:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Page:Evidera: Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Pelligra:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Guo:Celgene: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Preliminary Results from a Phase Ib Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Preliminary Results from a Phase Ib Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Pomalidomide + Low-Dose Dexamethasone Following Second-Line Lenalidomide-Based Therapy in Relapsed or Refractory Multiple Myeloma: A Phase 2 Study Investigating Efficacy and Safety

Background: Pomalidomide (POM) in combination with low-dose dexamethasone (LoDEX) is approved for the treatment (Tx) of patients (pts) with multiple myeloma (MM) who have had ≥ 2 prior lines of therapy, including lenalidomide (LEN) and a proteasome inhibitor. Although LEN and POM are both IMiD® immunomodulatory agents, preclinical studies have shown that LEN is not cross-resistant with POM (Ocio et al, Leukemia, 2015) and that LEN-resistant myeloma cells remain sensitive to POM (Lopez-Girona et al, Leukemia, 2012). Furthermore, sub-analyses of the MM-002 and MM-003 trials demonstrated that POM + LoDEX had comparable efficacy in pts refractory to their last prior Tx with LEN as in the overall pt population (San Miguel et al, Lancet Oncol, 2013; Richardson et al, Blood, 2014). Here, we present an updated analysis of MM-014, a single-arm, phase 2 trial of POM + LoDEX in pts with MM relapsed or refractory to LEN-based second-line therapy. Methods: Pts were ≥ 18 years old with a documented diagnosis of MM, measurable disease, 2 prior lines of Tx, and progressive disease after ≥ 2 cycles of second-line Tx with a LEN-based therapy. The Tx regimen was POM 4 mg/day on days 1-21 and LoDEX 40 mg/day (20 mg/day for pts > 75 years old) on days 1, 8, 15, and 22 of a 28-day cycle; thromboprophylaxis was mandatory. Responses were assessed using modified International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]). Secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Secondary primary malignancies (SPMs) were monitored and recorded as serious AEs regardless of relationship to Tx. Exploratory endpoints included measures to identify potential molecular, immune, and cellular biomarkers for POM + LoDEX response, resistance, or mechanism of action. Results: Of 51 enrolled pts (N = 85 planned), 16 (31.4%) remain on Tx, and 35 (68.6%) discontinued from Tx (n = 20 due to PD, n = 7 due to withdrawal by pt, and n = 2 each due to adverse event [AE], death, lack of efficacy, and other reasons). The median age was 68.0 years, and most pts (92.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1; 34 pts (66.7%) were refractory to their last Tx with LEN, and 37 (72.5%), 2 (3.9%), and 1 (2.0%) pts had prior Tx with bortezomib, carfilzomib, or ixazomib, respectively. A total of 33 pts (64.7%) had prior stem cell transplant. The median duration of the most recent prior LEN-containing Tx was 24.6 months, and the median study follow-up time was 11.4 months. The ORR was 31.4%, including 3.9% (n = 2) with complete response, 5.9% (n = 3) with very good PR, and 21.6% (n = 11) with PR. The clinical benefit rate (≥ minimal response) was 41.2%. Of the 16 pts who achieved ≥ PR, 12 (75.0%) have an ongoing response; median TTR in these pts was 1.9 months. The median DOR based on Kaplan-Meier estimates was not reached. The 1-year PFS, OS, and TTP rates were 60.2%, 87.4%, and 64.6%, respectively. Common (≥ 5%) grade 3/4 AEs included anemia (23.5%), neutropenia (13.7%), thrombocytopenia (9.8%), fatigue (7.8%), and infections (19.6%; including pneumonia [7.8%]). AEs of special interest (any grade) included pulmonary embolism (3.9%), deep vein thrombosis (2.0%), and peripheral sensory neuropathy (3.9%); no SPMs were observed. The immune subset analysis showed a significantly elevated proportion of CD3+/CD8+ T cells after Tx (cycle 3, 5, day 1) compared with baseline (37.6% vs 30.5% of total lymphocytes; P Conclusions: This updated analysis of the MM-014 trial demonstrates the safety and efficacy of POM + LoDEX in pts who were relapsed or refractory to their last prior Tx with LEN. Results suggest that POM + LoDEX can be used immediately following LEN-based therapy to treat pts with relapsed/refractory MM. The study has been amended to include a cohort of pts treated with POM + LoDEX + daratumumab. Investigations of additional biomarkers, high-risk genetic aberrations, clonal evolution, and minimal residual disease in MM-014 are currently underway. Disclosures Siegel:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Merck: Honoraria. Schiller:Incyte Corporation: Research Funding. Song:Otsuka: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaya:Celgene, Amgen, Takeda: Honoraria. Sebag:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reu:Celgene, Novartis and Takeda: Research Funding; Signal Genetics, Inc.: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Chung:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Qian:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria.

Matching-Adjusted Indirect Treatment Comparison of Bosutinib, Dasatinib, Nilotinib and Ponatinib on Survival for Second Line Chronic Phase Chronic Myeloid Leukemia Patients

Background: In clinical trials of second line and later line therapies for chronic myeloid leukemia (CML), to date only single arm trials have been conducted for the available treatments (i.e. Bosutinib, Dasatinib, Nilotinib and Ponatinib). These trials included heterogeneous patient populations in terms of line of treatment, stage of disease and other patient- and disease baseline characteristics that may impact the outcomes of the treatment. This hampers any direct or indirect comparisons of these second line CML treatments in terms of efficacy measures such as progression-free survival (PFS) and overall survival (OS). In this situation (i.e. lack of common comparator), matching-adjusted indirect treatment comparisons (MAICs) can be applied.Objective: The aim of this research was to compare the efficacy (PFS and OS) of Bosutinib, Dasatinib, Nilotinib and Ponatinib in second line chronic phase CML patients by means of MAICs. Patient data are reweighted such that their medians on demographic and clinical characteristics match those of the aggregated comparator trial, in order to adjust for cross-trial differences in those baseline characteristics. Outcomes of the reweighted patient level dataset are then compared with those of the aggregated comparator trial.Methods: A systematic literature review of second-line or later CML Phase II and Phase III clinical trials identified 2 trials for Bosutinib, 11 trials for Dasatinib, 8 trials for Nilotinib and 2 trials for Ponatinib. For the MAIC, only second line chronic phase trials with three or more years of follow-up (to allow for sufficient differentiation of treatments over time) were considered, resulting in 1 trial for Bosutinib (NCT00261846), 1 trial for Dasatinib (CA180-034), 1 trial for Nilotinib (NCT00109707) and no trials for Ponatinib. To adjust for cross-trial differences, patient data from the Bosutinib trial were subject to the inclusion and exclusion criteria reported in the comparator trials, and were weighted to match all available summary baseline characteristics reported in the 1 Dasatinib trial and the 1 Nilotinib trial. The baseline characteristics considered for reweighing were as follows: age, gender, Imatinib resistant/intolerant, disease duration, and prior stem cell transplantation. After the MAICs, PFS and OS were compared based on hazard ratios (HR) derived by Cox proportional hazard (PH) regressions using the reweighed Bosutinib dataset. The Cox PH assumption was tested with log cumulative hazard plots, Schoenfeld residuals and its corresponding statistical test. In case the PH assumption did not hold, Cox regressions with time varying coefficients were tested and the relative restricted mean survival time (RMST) was estimated.Results: Comparing Bosutinib to Nilotinib resulted in HRs for PFS and OS of 2.0 (<0.01) and 1.4 (p=0.109) respectively. When compared to Dasatinib, Bosutinib showed a non-significant HR of 1.3 (p=0.30) in favor of Bosutinib for OS and a significant 1.6 HR (p<0.01) for PFS. In the PFS and OS analyses compared to Dasatinib, the PH assumption was violated based on the statistical test or almost violated according to the visual plots. Therefore, we examined the relative restricted mean survival times, which were 1.123 (p=0.02) for PFS and 1.025 (p=0.41) for OS.Discussion: After performing MAICs to adjust for cross-trial differences in baseline characteristics, Bosutinib appeared to have a significantly greater PFS than Nilotinib (p<0.01). Based on the relative RMST analyses, Bosutinib also appeared to have a significantly greater PFS than Dasatinib, at the p<0.05 level. For OS the findings were numerically positive in favor of Bosutinib, but not statistically significant, compared to both. However, qualitatively, Bosutinib appears to be an equally effective second line chronic phase CML therapy. The greater PFS compared to Nilotinib and Dasatinib, especially at the end of the follow up period for Bosutinib, may translate into future OS benefits not yet observed.A limitation of our study is that we could only correct for observed differences between the trials, and not for unobserved ones. Also, the reweighing was performed for all relevant reported baseline characteristics; not all baseline characteristics were reported in all trials. Both limitations could have an impact on the outcomes and therefore the study conclusions. DisclosuresMuresan:Ingress-health Nederland BV: Employment. Mamolo:Pfizer Inc: Employment, Equity Ownership. Cappelleri:Pfizer Inc: Employment, Equity Ownership. Shapiro:Pfizer Inc: Employment, Equity Ownership. Crescenzo:Pfizer Inc: Employment. Su:Pfizer: Employment, Equity Ownership; Bristol Myers Squibb: Equity Ownership. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.

Final Results of the Chrysalis Trial: A First-in-Human Phase 1/2 Dose-Escalation, Dose-Expansion Study of Gilteritinib (ASP2215) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Final Results of the Chrysalis Trial: A First-in-Human Phase 1/2 Dose-Escalation, Dose-Expansion Study of Gilteritinib (ASP2215) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Phase IB/II Study of Lirilumab in Combination with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML)

Background: Inhibitory killer-cell immunoglobulin receptors (KIRs) negatively regulate NK cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK-mediated antitumor efficacy in AML patients in remission upon haploidentical stem cell transplantation (SCT) from KIR-mismatched donors (Ruggeri L et al., Science 2002). Blockade of KIR2DL1, 2 and 3 receptors induced augmented NK-cell mediated lysis of tumor cells (Romagne F et al., Blood 2009). Hypomethylating agents possess anti-leukemia activity and concomitantly alter immune regulation. Blockade of the KIR-receptors by lirilumab may improve response rates and abrogate immune-mediated resistance to hypomethylating agents.Patients and Methods: Pts are eligible if they have AML and failed prior therapy (including prior therapy with a hypomethylating agent), have adequate performance status (ECOG ≤ 2), and organ function. AZA was given at the dosage of 75mg/m2 on days 1-7; lirilumab was given on Day 8 at the dosage of 1 and 3 mg/kg in 2 consecutive cohorts of 6 pts each. Courses were repeated approximately every 4-5 weeks. No dose-limiting toxicities were observed and lirilumab 3mg/kg was established as the recommended phase 2-dose (RP2D) in combination with AZA. 9 additional pts have been treated at the RP2D. Responses were evaluated at the end of 3 courses of therapy.Results: To date, 21 pts (11 de novo, 10 secondary AML), median age 60 years (range, 33 - 89), 48% with adverse cytogenetics, median prior therapies of 3 (range, 1-8), and prior allogeneic SCT in 6 (28%) have been enrolled. All 21 pts had baseline next generation sequencing for 28-genes and frequently identified mutations included TP53 (n=6), TET2 (N=6), ASXL1 (n=5), RUNX1 (n=5), EZH2 (n=3), DNMT3A (N=2), and CEBPA (n=2). 12 pts are ≥ 3 months into therapy and evaluable for response at this time: 1 achieved complete remission (CR), 1 achieved complete remission with insufficient count recovery (CRi), 2 (17%) had ≥50% bone marrow (BM) blast reduction, 2 (17%) had hematologic improvement (HI) > 6 months, and 6 (50%) had progressed. Nine pts were too early for response assessment. The 4- and 8-week mortality is 0 and 5%, respectively. The median duration of response, overall survival (OS) and event-free survival for the 12 evaluable pts were 2.5 months (range, 1.1 - 3.0) 4.4 months and 3.2 months, respectively.Grade 3/4 toxicities irrespective of causality were similar to those seen with AZA based therapies in salvage patients included 15 episodes of neutropenic infections, 6 pneumonia, 1 UTI, 1 skin infection, 2 abdominal pain, and 1 mucositis. Immune mediated toxicities were observed in 3 (14%) pts (1 pneumonitis Grade 3, 1 colitis Grade 2, 1 infusion reaction Grade 2), respectively. The immune mediated toxicities responded rapidly to steroids and all 3 pts could be rechallenged safely with lirilumab. Six pts were postSCT and no Grade 3/4 GVHD flares were noted. No pts have come off study due to toxicities and the azacytidine or lirilumab were not discontinued in any pts due to toxicities.Multicolor flow-cytometry studies and Mass-cytometry (CyTOF) studies are being conducted by the Immunotherapy Platform on baseline and on-treatment BM aspirate (end of cycle 1, 2, 4, 8) and peripheral blood to assess NK- and T-cell costimulatory markers.Conclusion: Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML with poor risk features, including pts with post-allogeneic SCT relapse. The efficacy data are still preliminary. AZA with lirilumab is being investigated in earlier salvage in AML and frontline and salvage settings in myelodysplastic syndrome. DisclosuresDaver:Kiromic: Research Funding; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Phase 1b Study of Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Results from the Ongoing Keynote-013 Trial

Phase 1b Study of Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Results from the Ongoing Keynote-013 Trial

Predictors of Overall Survival (OS) in Patients with Multiple Myeloma (MM) Initiating First- and Second-Line Treatment in the Czech Republic

MM is a heterogeneous disease. The International Staging System (ISS) and the revised-ISS (R-ISS) can be used to stratify patients in terms of risk of mortality in newly-diagnosed MM (NDMM) however; there is less understanding of the predictors of OS in the relapsed setting. This retrospective analysis of the Registry of Monoclonal Gammopathies database, which covers ~80% of all Czech patients with MM, was designed to explore how predictors of OS differ between initiation of first- and second-line treatments, in order to further understand patient heterogeneity as the disease progresses.Eligible patients initiated first-line treatment for symptomatic MM between May 2007 and April 2016. Factors considered prognostic of OS in both NDMM and relapsed/refractory MM were identified from targeted literature searches. Predictors of OS in second-line treatment included historical parameters that reflect outcomes to previous therapy. OS data was then fitted with multiple Cox-regression models. Backward selection was performed using Akaike's Information Criterion (AIC) as selection criterion.Patient characteristics at both first- (N=3027) and second-line (N=1418) treatment initiation are presented in Table 1. Comparison of these characteristics shows that as patients progress, on average their profile becomes less severe (e.g. ISS stage III 28% vs 20% in first- and second-lines, respectively), mainly explained by the dropout rate between first- and second-line treatment (Raab et al 2016) as patients either died or did not continue therapy due to adverse prognosis.Median OS (95% CI) from initiation of first- and second-line treatment was 49.9 (46-54) and 27.6 (25-30) months. Results of OS predictive variables are shown in Table 2. Predictors of OS differ between initiation of first-line versus second-line therapy, both in terms of type of predictor as well as strength. At initiation of first-line, calcium level, bone lesions and bone marrow aspiration cytology were not significant predictors of OS, however they became significant at initiation of second-line or were selected by backward selection procedure. At initiation of second-line, historical parameters defining outcomes of prior treatments remained strong predictors, however only refractory status to prior bortezomib [HR=1.626 (1.267-2.087 p=0.0001)] and time to next treatment (TTnT) [HR=1.280 (1.051-1.559, p=0.014)] were significant predictors of OS. The significance of prediction of age and Eastern Cooperative Oncology Group (ECOG) performance status remained in both settings, with a lower impact of age in second-line treatment. Data for cytogenetics was not collected for initiation of second-line, however it is included in the R-ISS component. Although only measured at diagnosis, it remained a significant predictor in both settings (N.B. this variable had 82% missing values). Restaging of ISS at initiation of second-line was predictive, especially for those ISS III vs ISS I, HR=1.56 (1.23-1.97 p=0.0002). Additionally, lactate dehydrogenase (LDH), which is also a component of R-ISS was significant in both settings with as stronger effect in second-line. Elements normally considered predictive of OS at initiation of second-line did not appear in the final model: prior stem-cell transplant status or time-to-progression of previous therapy, perhaps explained by age and TTnT, respectively. Creatinine level was not significant at initiation of second-line, perhaps as patients with renal impairment during first-line treatment may not receive second-line treatment.This real-world analysis of data from Czech patients revealed that predictors of OS differ between initiation of first- and second-line treatments. Prediction of OS in the relapsed setting should consider patient-related factors (age, ECOG), factors reflecting the disease activity and severity (LDH, bone lesion, calcium level) as well as historical elements, including those that were dependent on patient experience in the first treatment line (treatment response and duration of response). Additionally, there seems to be value in reclassification of patients in terms of severity at the relapse setting in order to improve prognosis and treatment selection in the relapsed setting. [Display omitted] [Display omitted] DisclosuresHájek:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; BMS: Honoraria; Janssen: Honoraria. Jiri:Amgen: Consultancy. Walter:Amgen: Consultancy. Maarten:Amgen: Consultancy. Lucy:Amgen: Employment, Other: Amgen Stock. Marco:Amgen: Employment, Other: Holds Amgen Stock. Lucie:Amgen: Consultancy. Sebastian:Amgen: Employment, Other: Holds Amgen Stock.

Abstract 4895: Hodgkin lymphoma patients demonstrate evidence of chronic activation/exhaustion in circulating T cell subsets

Abstract Background: In Hodgkin lymphoma (HL) the malignant Hodgkin Reed-Sternberg (HRS) cells comprise only a small fraction of the total cellular tumor population, which orchestrate an inflammatory microenvironment of reactive cells that propagate a permissive milieu for HL growth. This HL-mediated immune suppression may have effects that extend beyond the tumor microenvironment. Previously we have shown that the circulating T cells of HL patients show high expression of the receptor programmed death-1 (PD-1). Here wecharacterize the systemic immune profile of 20 HL patients with newly diagnosed (ND) or relapsed (R) disease. Methods: Informed consent obtained from patients with ND (n = 14) or R (n = 6) HL treated since January of 2013. Blood samples were drawn pre-treatment, and at sequential time-points during therapy. Cryopreserved PBMCs were thawed then evaluated with multi-color flow cytometry. Cells were stained with fixable viability dye (eBioscence); then stained with fluorescent-conjugated antibodies. For intracellular staining, cells were fixed and permeabilized using FOXP3 staining kit (eBioscience) then stained with intracellular antibodies. Stained cells were analyzed using LSRII flow cytometer (BD Bioscience) and FlowJo software (Tree Star). The following anti-human antibodies were used: CD3, CD4, CD8, CD25, CD160, CD45RO, CD27, HLA-DR, PD-1,FOXP3 and Helios, (Biolegend). Singlet lymphocytes were gated based on forward and side scatter properties. Dead cells were excluded based on viability dye. Patient samples were compared to normal controls matched for age and sex (n = 20). Results: The median HL patient age was 38 (range: 20-90 years). Twelve of the HL subjects were male and 8 were female. All but 1 ND patient were treated with upfront ABVD. Two out of 6 R patients had prior stem cell transplant (SCT), but were not on immunosuppression. Thirteen patients (12 ND, 1 R) responded to therapy (11 CR and 2 PR); 4 patients (1 ND, 3 R) progressed on therapy or had stable disease, 2 patients do not have disease status confirmed. HL patients displayed distinct circulating immune profile compared to normal age matched controls, with increased circulating CD4 and CD8 effector cells and a decrease in CD8 central memory cells. The proportion of CD4 or CD8 effector memory T cells expressing CD160+ and PD1+ CD4 effector memory cells, were also highly significantly increased in HL patients. In contrast, a decreased percent of bona fide CD4+ regulatory T cell subset (Foxp3+Helios) was found in HL patients. Together these findings suggest that the systemic immune profile in HL patients is perturbed towards severe chronic activation/exhaustion of T cells. Conclusion: HL patients have evidence of chronic activation/exhaustion in their central memory T cells, suggesting that ineffective immune clearance of the HRS cells may be a systemic phenomenon. This underscores the rationale for immune targeted therapy in HL patients. Citation Format: Catherine S. Diefenbach, Bruce Raphael, Kenneth Hymes, Michael Grossbard, Tibor Moskovits, David Kaminetzky, Meghan Mcshea, Peter Martin, Jia Ruan, Lina Kozhaya, Maryam Bonakdar, Cem Abidoglu, John Leonard, Derya Unutmaz. Hodgkin lymphoma patients demonstrate evidence of chronic activation/exhaustion in circulating T cell subsets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4895.

Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL.

3011Background: Targeted immunotherapy with chimeric antigen receptor (CAR)-modified T cells can produce potent anti-tumor responses. We previously reported complete remissions (CR) and prolonged persistence in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of 59 children with r/r ALL. Methods: T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/CD28 beads, and then infused at a dose of 107 to 108cells/kg with a transduction efficiency of 2.3-45%. 54/59 patients received lymphodepleting chemotherapy the week prior to cell infusion. Results: Of 59 patients aged 20mo-24y with CD19+ ALL, 44 had detectable disease prior to CTL019 cell infusion, while 15 were MRD-. 39 were treated for relapse after prior stem cell transplant (SCT). 15 patients had ...

Phase I study of single agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).

2046Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for patients with recurrent/refractory disease. Response rates range between 30-60% with a progression free survival (PFS) of 2-6 months. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates ibrutinib in patients with recurrent/refractory (r/r) PCNSL and secondary CNS lymphoma (SCNSL). Methods: Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, KPS ≥ 50, normal end-organ function, and unrestricted number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Ten patients were enrolled (3 at 560 mg; 7 at 840 mg). Median age was 70 (range 21-80); 7 were women. Median ECOG was 1 (0: 1, 1: 5, 2: 4). 70% had PCNSL and 30% SCNSL. Six had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 1 both. Patients were highly pretreated: 2 (both SCNSL) had prior stem cell transplant; 3 (2 PCNS...

Evaluation of gemtuzumab ozogamycin associated sinusoidal obstructive syndrome: Findings from an academic pharmacovigilance program review and a pharmaceutical sponsored registry

BackgroundIn 2000, the Food and Drug Administration (FDA) approved gemtuzumab ozogamycin for monotherapy for older patients with relapsed AML. A 0.9% rate of hepatic sinusoidal obstructive syndrome (SOS) was noted in licensing trials. In 2001, FDA received reports of 14 GO-associated SOS cases from MD Anderson Cancer Center. A State of South Carolina/National Cancer Institute funded pharmacovigilance program and a manufacturer sponsored registry independently evaluated this concern. MethodsThe manufacturer’s registry and the academic program focused on risk factors and incidence of GO-associated SOS in routine clinical practice and clinical trial settings, respectively. Comparisons were made of findings and dissemination efforts from the two studies. ResultsRetrospective analysis of clinical trials by the academic initiative identified 99 cases of SOS among 221 GO-treated stem cell patients and 649 patients who did not undergo HSCTs. SOS rates were 3% when GO was administered at doses ≤6mg/m2 as monotherapy or with non-hepatotoxic agents; 28% when administered with 6-thioguanine, a hepatotoxic agent; 15% when administered as monotherapy at doses at a dose of 9mg/m2, and between 15% and 40% if a stem cell transplant (SCT) was performed within 3 months of GO administration. Death from SOS occurred in 33% of the cases. The manufacturer’s registry prospectively evaluated 482 GO-treated patients who received a mean dose of 7.8mg/m2. Overall, 41% received concomitant chemotherapy, 18% had undergone prior SCT, 9.1% developed SOS, and death from SOS occurred in 60% of the SOS cases. Findings from each initiative were disseminated at national conferences and in peer-reviewed manuscripts beginning in 2003. ConclusionRetrospective review of clinical trials, case series, and FDA reports and prospective registries can provide important information on safety signals initially identified in licensing trials.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) Monotherapy for Relapsed/Refractory Multiple Myeloma: Phase 1 Preliminary Results

Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM.Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS).Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax.Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table).Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable.Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. [Display omitted] DisclosuresKumar:Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

A Phase I-II Study of the Combination of Bendamustine and Pomalidomide with Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma.

BackgroundBendamustine, a bifunctional mechlorethamine derivative with alkylating properties and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). Bendamustine in combination with lenalidomide, thalidomide, and bortezomib have had high response rates and good tolerability. We combined bendamustine and pomalidomide with dexamethasone (Ben-Pom-d) and hypothesized that this regimen would be highly effective in patients with RRMM. Dose-escalation started with 120mg/m2 bendamustine/3mg pomalidomide [or 4mg in the cohort 2]/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD was 120mg/m2 bendamustine/3mg pomalidomide/40 mg dexamethasone. Here, we report our findings to date from the phase I/II trial of Ben-Pom-d in patients with RRMM (NCT01754402).Methods The primary objective of the phase I portion was to determine the MTD. Data for overall response, progression free survival, and overall survival, includes all patients treated on the phase I and II portions of the study. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Patients had to be pomalidomide naïve. Treatment consisted of oral pomalidomide once daily on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria.Results A total of 9 patients were enrolled in the phase I portion. The MTD was the starting dose level (bendamustine 120 mg/m2, pomalidomide 3mg, dexamethasone 40 mg). In Phase II we enrolled an additional 16 patients resulting in a total study population of 25 patients evaluable for toxicity and 22 for efficacy, with 6 still receiving treatment.The median age was 65 years (range 43-81), 46% were male. The median number of prior regimens was 3 (range 2-6), median time from diagnosis is 3.9 years (range 1.1-9.10 years), 88% of patients had a prior stem cell transplant, 100% had prior bortezomib, 20% had prior carfilzomib and all were lenalidomide-refractory. Fifteen patients had high risk cytogenetic, including 8 patients with del17. Patients received a median of 6 cycles of therapy (range 1-18 cycles). Best response assessments in 22 evaluable patients for efficacy, showed 5 (23%) VGPR, 12 (55%) PR, 3 (14%) MR, and 2 (9%) SD, for an ORR of 77% and a ≥MR rate of 91%. The median follow-up of survivors is 10 months (range: 2-19+ months). Median PFS and OS were 4.5 months (range 1-15+ months) and 9.5 months (range 2-19+ months), respectively, for the entire cohort with 13 of 22 still alive in follow-up. The Median PFS for patient with del 17 is 5.5 months (range 2-15 months) with >MR rate of 88%.During the first cycle, 3 patients of all 25 evaluable enrolled experienced a DLT at the different doses, including 1 nausea/vomiting [cohort 1], and 2 with rash and fever in cohort 2. The therapy was tolerated well, but toxicities reported at any point while on therapy included 32% grade 4 neutropenia, 16% grade 4 thrombocytopenia, and half the patients requiring delay of subsequent cycles due to cytopenias and 17 of 22 (77%) had a dose reduction of pomalidomide per protocol guidelines at some point in the continuation cycles. The major non-hematologic Grade ≥3 drug-related AEs that occurred included febrile neutropenia in 12%, grade 3 mucositis in 8%, grade 3 pneumonia 16% and grade 4%, and grade 4 sepsis 4%.Conclusions The Ben-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 77%; ≥MR rate of 91%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure. Therapy is ongoing for many and longer follow-up is needed to better assess the true durability of this approach. DisclosuresGasparetto:Onyx: Honoraria, Other: Advisory Board; Millennium/takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; teva: Other: spouse-ad board and speaker bureau. Off Label Use: Bendamustine-pomalidomide-dexa for treatment of relapsed myeloma. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Rao:novartis: Other: ad board; amgen: Other: ad board; Boehringer-Ingelheim: Other: Advisory Board. Tuchman:celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium/takeda: Honoraria, Research Funding, Speakers Bureau.

Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Fludarabine and Cytarabine in Pediatric Patients with Relapsed or Refractory AML

Background and Purpose: Although novel approaches to the treatment of acute myeloid leukemia (AML) are urgently needed, the heterogeneity of AML and the paucity of known actionable targets indicate that there is an important need for broadly active treatment approaches that are not limited to specific genetic subtypes. Selinexor, an oral selective inhibitor of nuclear export, inhibits XPO1 and causes differentiation and apoptosis of a variety of AML subtypes while sparing normal hematopoiesis. We therefore undertook a pilot study to determine the safety and to explore the efficacy of selinexor in combination with fludarabine and cytarabine in pediatric patients with relapsed leukemia.Patients and Methods: Twelve children and adolescents with relapsed or refractory AML (n=10) or mixed phenotype leukemia (n=2) have been enrolled on the study to date. Four patients previously received only chemotherapy, whereas eight had undergone at least one prior stem cell transplant. High-risk features included t(6;9), t(6;12), t(4;11), -7 (2 cases), and megakaryoblastic leukemia. Selinexor, initially at 30 mg/m2/dose, was given orally on days 1, 3, 8, 10, 22, and 24 and escalated according to a rolling-6 design. Fludarabine (30 mg/m2) and cytarabine (2 g/m2) were administered on days 15-19.Results: Among 11 patients who completed at least one cycle and were evaluable for toxicity and response, 3 were treated at dose level 1 (30 mg/m2), 3 at dose level 2 (40 mg/m2), 4 at dose level 3 (55 mg/m2), and 1 at dose level 4 (70 mg/m2). No dose-limiting toxicities were observed at any dose level. The most common Grade 3 non-hematologic toxicity related to selinexor was hyponatremia, which was observed in 10 patients and easily corrected in all cases. As expected, the combination of selinexor plus fludarabine and cytarabine resulted in Grade 3 neutropenia and thrombocytopenia in all patients. Mean pharmacokinetic parameters indicate that plasma exposure is generally dose proportional across selinexor doses, with no apparent accumulation. Plasma exposure in pediatric patients is similar to adult patients treated in phase I trials. Inhibition of XPO1 was assessed by qRT-PCR of XPO1, which is upregulated at the RNA level in response to XPO1 protein inactivation (PDn). Six of the first seven patients enrolled on the trial demonstrated at least 2-fold induction of XPO1 that persisted for at least 48 hours (see figure), indicating prolonged inhibition of the protein by selinexor. The overall response rate in this group of heavily pretreated, relapsed, and refractory patients was 55%. Five patients achieved complete remission (4 with complete count recovery) and 1 had a partial response. Eight of the 11 patients underwent subsequent stem cell transplantation. A trend toward stronger and persistent XPO1 inhibition (measured by PDn) was observed among patients who achieved CR compared to those who did not.Conclusion: Selinexor, given in combination with fludarabine and cytarabine, is tolerable in pediatric patients with relapsed leukemia. Selinexor pharmacokinetic parameters are generally dose proportional and are similar to those seen in adult patients. Most patients demonstrate XPO1 target inhibition. Response rates are encouraging and will be further explored in the Phase II portion of this trial. [Display omitted] DisclosuresKaufman:Karyopharm Therapeutics Inc: Employment. Klebanov:Karyopharm Therapeutics Inc: Employment. Ellis:Karyopharm Therapeutics Inc: Employment. Landesman:Karyopharm Therapeutics: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Rashal:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm: Employment, Equity Ownership.

Lenalidomide in Combination with Bendamustine for Patients with Chemorefractory Hodgkin Lymphoma: Final Results of the Leben Multicenter Phase 1/2 Study

BackgroundImproving strategies for patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) who fail stem cell transplantation (SCT) or are unsuitable for the procedure remains an essential need. Lenalidomide and bendamustine are active and well tolerated as single agents in recurrent HL, with overall response rates (ORR) of 30% to 53% [Fenhinger, 2012; Corazzelli, 2012; Moskowitz, 2012].These agents independently frame different targets on tumor and microenvironment cells and may cooperate to override disturbed immunologic pathways and circumvent drug resistance in HL. In a Bayesian, multi-center, open label phase 1/2 study, we investigated for safety and efficacy the combination of continuous lenalidomide with weekly bendamustine (ClinicalTrials.gov # NTC01412307).MethodsThe study aimed at defining the optimal daily dose of continuous lenalidomide (10, 15, 20 or 25 mg) as combined, in a 28-day cycle, to weekly fixed-dose bendamustine (60 mg/m2; d 1, 8, 15). The dose-finding algorithm proceeded in cohorts of 3 pts, based on anticipated efficacy and toxicity pairs of probability (Thall & Cook, Biometrics 2004). Trade-offs between response [Cheson 2007 criteria] and dose-limiting toxicity [CTCv3.0 grade (G) >3 lasting >2 weeks] were assessed after 2 cycles (day +56) and pts were planned to receive up to 6 total courses, unless progression or unacceptable toxicity occurred. ORR and progression-free survival (PFS) were additional endpoints.ResultsThirty-six pts (69% male) with a median age of 31 yrs (r 19-75) were enrolled. The median number of prior therapies was 4 (r 1-9) and the median time from upfront treatment was 24 mo.s (r 7-118). Twenty-six pts (72%) had primary refractory disease after ABVD, 16 pts (44%) failed prior SCT [single (n=7) or tandem (n=3) ASCT, tandem ASCT/alloSCT (n=6)]. Fifteen pts (42%) had previously received a median of 5 cycles (r 2-8) of brentuximab vedotin (BV) and 3 pts were already given bendamustine (>3 courses). Overall, 23 pts (64%) were refractory to most recent therapy. Eff/Tox trade-offs at cycle 2 showed that 73% of pts had response w/o toxicity, 19% had no response w/o toxicity, 6% had response with toxicity and 2% had no response with toxicity. With such Eff/Tox profiles, the study algorithm did not prompt any dose escalation for lenalidomide after the first 18 pts and the initial dose level (10 mg) was adopted for the expansion phase. A total of 156 LeBen cycles were administered, and pts received a median of 4 courses (r 1-6). Overall, 16 cycles were delayed due to G3/G4 thrombocytopenia (n=6), G4 neutropenia (n=3), G3 pneumonia (n=3), G3 respiratory infection (n=2), G2 phlebitis (n=1), G2 supraventricular arrhythmia (n=1). Two patients discontinued treatment, while in PR and CR after 4 courses, due to protracted (>2 weeks) thrombocytopenia. No G4 extra-hematological toxicity was observed. The complete response (CR) rate was 44% (16/36) with an ORR of 75% (27/36; 95% CI, 59-86). Notably, substantial CR and PR rates were achieved after LeBen regardless of primary refractoriness, SCT and BV failure (Table). Most CRs (14/16) were obtained within the first 4 cycles; 6 responders (4 CRs and 2 PRs) underwent SCT. Median PFS was 3.2 mo.s (r 1.5-5.4) for pts with progressive (PD) or stable disease (SD) and 11.4 mo.s (r 4-31) for those achieving CR/PR. Median overall survival for the entire cohort was 24 mo.s. Overall, complete responders (including 6 pts consolidated with SCT) had a 2-year disease-free survival of 41% (median, 14.3 mo.s).ConclusionsThe innovative schedule of the Leben combination is safe, yields high response rates in heavily pretreated and primary refractory HL pts, including SCT and BV failures, and steps over the 'single agent' activity of its components. Due to its immunomodulatory potential the Leben platform is amenable to further upgrading through lenalidomide maintenance, combination with immune checkpoint inhibitors and BV.Table 1Efficacy resultsResponsesno. (%)All ptsRefractory to upfront therapyRefractory to most recent therapyFailure after SCTFailure after ASCTFailure after AlloSCTFailure after BVFailure after SCT and BVFailure after bendamustineNo BV(n=36)(n=26)(n=23)(n=16)(n=10)(n= 6)(n=15)(n=8)(n=3)(n=21)CR16 (44)11 (42)8 (35)8 (50)6 (60)2 (33)5 (33)3 (37)011PR11894224207SD2221011111PD7543215222CR+PR27 (75)19 (73)17 (74)12 (75)8 (80)4 (66)9 (60)5 (62)018 (86) DisclosuresPinto:Takeda, Celgene, Roche, TEVA: Honoraria; Takeda: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Results from a Phase 1 Study and Expanded Cohort of an Interrupted Dosing Schedule of the Aurora Kinase a Inhibitor MLN8237 Combined with Vorinostat in Lymphoid Malignancies

BackgroundMLN8237 is an oral inhibitor of aurora kinase A (AURKA) that causes mitotic spindle defects, mitotic delay, and apoptosis in lymphoma cell lines and mouse models. Human studies have shown promising responses in hematologic malignancies. Vorinostat is an oral HDAC inhibitor that is FDA-approved for cutaneous T-cell lymphoma, and is under study in other lymphomas. AURKA inhibitors in combination with vorinostat show synergistic pro-apoptotic effects in vitro in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines (Kretzner 2011, Cancer Res 71:3912). Our phase I multicenter study assessed the safety and tolerability of MLN8237 combined with vorinostat in patients with lymphoid malignancies [NCT01567709] and determined the maximum tolerated dose (MTD) to be 20 mg twice daily (BID) of MLN8237 and 200 mg BID of vorinostat orally in an interrupted dosing schedule (Schedule II). We have recently completed accrual to an expanded cohort at MTD and report preliminary data on our secondary endpoints among patients treated on Schedule II of this study.MethodsEligible patients were ≥18 years old with relapsed or refractory (r/r) lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ≥1500/µL, platelets ≥100,000/µL, and adequate kidney and liver function. Secondary endpoints were toxicities, clinical response, pharmacokinetic (PK) analysis, and correlative studies. A 3+2 modified rolling-6 design was employed to determine the MTD. Enrollment was initiated on a continuous dosing schedule (Schedule I) that was poorly tolerated, with adverse events (AEs) on dose levels 1 and 2 leading to many dose delays primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20 to 50 mg BID on days 1-3 and 8-10, and vorinostat given at 200 mg BID on days 1-5 and 8-12 of a 21-day cycle.ResultsWe treated 25 patients (11 DLBCL, 7 HL, 3 FL, 2 MCL, 1 PTCL, 1 NK/T cell) on the interrupted dosing Schedule II. Median age was 59 years (range 26-78). Mediannumber of prior therapies was 4 (range 1-10); 9 patients (36%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20 mg BID for MLN8237 and 200 mg BID for vorinostat on the interrupted schedule. The commonest (>5%) ≥ grade 3 drug-related AEs were neutropenia (52%), thrombocytopenia (44%), leukopenia (44%), anemia (28%), lymphopenia (24%), febrile neutropenia (12%), oral mucositis (8%), diarrhea (8%), and lung infection (8%). There were no study-related deaths. 4 patients stopped treatment due to AEs and 13 due to progressive disease (PD). 2 patients achieved complete remission (CR); both had DLBCL, and both halted therapy after completing 2 further cycles of treatment post-CR. They both remain in CR (18 months and 1 month at data lock). 1 patient had a partial response (PR), and 8 patients maintained stable disease (SD). PKs demonstrated a clearance of 230 L/h (sd=495) and 2.94 L/h (sd=1.57) for vorinostat and MLN8237, respectively. Archived baseline biopsies are being analyzed to determine AURKA expression. Six fresh paired tumor biopsies were obtained before and on-treatment in the expanded cohort at MTD for correlative studies.ConclusionsMLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted dosing schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20 mg BID on days 1-3 and 8-10, combined with vorinostat at 200 mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs were hematologic and gastrointestinal. Promising responses were seen in several patients, especially those with DLBCL, which support phase 2 exploration of this therapy in patients with intermediate-high grade NHL. PK analysis suggests that combination therapy exposures are similar to single agent exposure. Correlative studies done in a 12-patient expanded cohort will be presented. [Trial supported in part by UM1CA186717]Table 1Schedule II:MLN8237 (mg)/ Vorinostat (mg)# of patients treated# of cycles completed Median (range)# of dose limiting toxicities (DLT)DLT DescriptionBest responseDose level 1 (30/200)73 (0-18)21 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring transfusion1 CR, 3 SD, 2 PD, 1 N/ADose level -1 (20/200)182 (0-14)01 CR, 1 PR, 5 SD, 8 PD, 3 too early to assess DisclosuresSiddiqi:Kite pharma: Other: attended advisory board meeting; Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau. Off Label Use: Vorinostat is only FDA-approved for CTCL but in this study it is being used in conjunction with MLN8237 (not FDA-approved) for all lymphomas.. Beumer:Millenium: Other: Research support. Forman:Mustang Therapeutics: Research Funding.

Phase II Study of the Fondazione Italiana Linfomi on Gemcitabine Plus Romidepsin (GEMRO Regimen) in Relapsed and Refractory Peripheral T-Cell Lymphoma Patients

Introduction. Relapsed and primary refractory peripheral T-cell lymphomas (PTCL) show a dismal outcome, with a 5-year overall survival of only 30%. There is no standard salvage chemotherapy for these patients. Gemcitabine was proved to be an effective monotherapy, yelding 60-70% overall response rates in patients with advanced heavily pre-treated disease. Romidepsin, a histone deacetylase inhibitor recently approved by Food and Drug Administration, has demonstrate an overall response rate (ORR) of 30% and a complete response (CR) rate of 16%. We have recently designed a multicentric trial to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed or refractory PTCL, looking for a potential synergistic effect of the two drugs.Methods. Twenty relapsed/refractory PTCL patients were included in a multicentric, prospective phase II trial which contemplated an induction with romidepsin 12 mg/m2 intravenously (i.v.) on days 1, 8, 15, and gemcitabine, 800 mg/m2 i.v. on day 1 and 15, for 6 cycles, each cycle to be repeated every 28 days. After the induction phase, patient who obtained at least a partial remission (PR) proceeded onto romidepsin maintenance at the dose of 14 mg/m2 i.v. until disease progression. The primary endpoint was to evaluate the efficacy of GEMRO regimen after the induction phase, as assessed by complete response (CR) rate; safety assessment was regarded as a secondary objective. The trial was registered under EudraCT (2012-001404-38).Results. Twenty patients have been recruited for this study. At present time, all patients underwent the induction phase and are evaluable for response and toxicity. The median age of patients was 55 years (range, 24-77). According to histology, 10 patients had PTCL not otherwise specified, 9 had an angioimmunoblastic T-cell lymphoma, 1 had a kinase negative anaplastic large cell lymphoma. The median number of prior therapies was 2 (range, 1-4); 7/20 (35%) patients had failed a prior stem cell transplant. Nineteen out of 20 (95%) patients presented with advanced stage. At the end of induction phase, the ORR was 31% including 2 CRs and 3 PRs. One of the 2 CR patients discontinued the treatment after 4 cycles due to cardiac toxicity, however maintaining a continuous CR with a follow up of 2 years. The other CR patient is still on treatment in maintenance phase. Grade ≥3 adverse events were represented by thrombocytopenia (60%), neutropenia (50%), and anemia (20%).Conclusions. To date, data failed to show a superiority of the GEMRO combination regimen over single agent romidepsin as salvage therapy for refractory or relapsed PTCL patients. More mature data and an adequate follow-up will be required to better understand the role of this combination regimen. DisclosuresZinzani:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.